Transvascular nerve stimulation apparatus and methods

ABSTRACT

Electrode structures for transvascular nerve stimulation combine electrodes with an electrically-insulating backing layer. The backing layer increases the electrical impedance of electrical paths through blood in a lumen of a blood vessel and consequently increases the flow of electrical current through surrounding tissues. The electrode structures may be applied to stimulate nerves such as the phrenic, vagus, trigeminal, obturator or other nerves.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/012,013, filed Jun. 19, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/252,687, filed Aug. 31, 2016, now U.S. Pat. No.10,022,546, issued Jul. 17, 2018, which is a continuation of U.S. patentapplication Ser. No. 14/792,006, filed Jul. 6, 2015, now U.S. Pat. No.9,566,436, issued Feb. 14, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/448,734, filed Jul. 31, 2014, now U.S. Pat. No.9,108,059, issued Aug. 18, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/044,466, filed Oct. 2, 2013, now U.S. Pat. No.9,220,898, issued Dec. 29, 2015, which is a continuation of U.S. patentapplication Ser. No. 12/524,571, filed Jul. 25, 2009, now U.S. Pat. No.8,571,662, issued Oct. 29, 2013, which is a 371 national stageapplication of PCT Patent Application No. PCT/CA2008/000179, filed Jan.29, 2008, which claims priority from U.S. Provisional Patent ApplicationNo. 60/887,031, filed Jan. 29, 2007. The entirety of each of the aboveapplications is incorporated herein by reference.

TECHNICAL FIELD

The invention relates to neurophysiology and in particular to apparatusand methods for stimulating nerves through the walls of blood vessels.Aspects of the invention provide electrode structures that may bedeployed within blood vessels to stimulate nerves passing near the bloodvessels; nerve stimulation systems; and methods for nerve stimulation.Aspects of the invention may be applied for restoring breathing,treating conditions such as chronic pain, and other uses involving nervestimulation. Aspects of the invention may be applied in the treatment ofacute or chronic conditions.

BACKGROUND

Nerve stimulation can be applied in the treatment of a range ofconditions. The nerve stimulation may be applied to control muscleactivity or to generate sensory signals. Nerves may be stimulated bysurgically implanting electrodes in, around or near the nerves anddriving the electrodes from an implanted or external source ofelectricity.

The phrenic nerve normally causes the contractions of the diaphragm thatare necessary for breathing. Various conditions can prevent appropriatesignals from being delivered to the phrenic nerve. These include:

-   -   chronic or acute injury to the spinal cord or brain stem;    -   Amyotrophic Lateral Sclerosis (ALS);    -   disease affecting the spinal cord or brain stem; and,    -   decreased day or night ventilatory drive (e.g. central sleep        apnea, Ondine's curse).        These conditions affect significant numbers of people.

Mechanical ventilation may be used to help patients breathe. Somepatients require chronic mechanical ventilation. Mechanical ventilationcan be lifesaving but has a range of significant problems. Mechanicalventilation:

-   -   tends to provide insufficient venting of the lungs. This can        lead to accumulation of fluid in the lungs and susceptibility to        infection.    -   requires apparatus that is not readily portable. A patient on        ventilation is tied to a ventilator. This can lead to atrophy of        muscles (including breathing muscles) and an overall decline in        well being.    -   can adversely affect venous return because the lungs are        pressurized.    -   interferes with eating and speaking.    -   requires costly maintenance and disposables.

Phrenic nerve pacing uses electrodes implanted in the chest to directlystimulate the phrenic nerve. The Mark IV Breathing Pacemaker Systemavailable from Avery Biomedical Devices, Inc. of Commack, N.Y. USA is adiaphragmatic or phrenic nerve stimulator that consists of surgicallyimplanted receivers and electrodes mated to an external transmitter byantennas worn over the implanted receivers. Implanting electrodes andother implantable components for phrenic nerve pacing requiressignificant surgery. The surgery is complicated by the fact that thephrenic nerve is small (approx. diameter 2 mm) and delicate. The surgeryinvolves significant cost.

Laproscopic diaphragm pacing being developed by Case Western ReserveUniversity bio-medical engineers and physician researchers is anothertechnique for controlling breathing. Devices for use in Laproscopicdiaphragm pacing are being developed by Synapse Biomedical, Inc.Laproscopic diaphragm pacing involves placing electrodes at motor pointsof the diaphragm. A laparoscope and a specially designed mappingprocedure are used to locate the motor points.

References that in the field of nerve stimulation include:

-   Moffitt et al., WO 06/110338A1, entitled: TRANSVASCULAR NEURAL    STIMULATION DEVICE;-   Caparso et al., US2006/0259107, entitled: SYSTEM FOR SELECTIVE    ACTIVATION OF A NERVE TRUNK USING A TRANSVASCULAR RESHAPING LEAD;-   Dahl et al., WO 94/07564 entitled: STENT-TYPE DEFIBRILLATION    ELECTRODE STRUCTURES;-   Scherlag et al., WO 99/65561 entitled: METHOD AND APPARATUS FOR    TRANSVASCULAR TREATMENT OF TACHYCARDIA AND FIBRILLATION;-   Bulkes et al., US2007/0288076A1 entitled: BIOLOGICAL TISSUE    STIMULATOR WITH FLEXIBLE ELECTRODE CARRIER;-   Weinberg et al., EP 1304135 A2 entitled: IMPLANTABLE LEAD AND METHOD    FOR STIMULATING THE VAGUS NERVE;-   Moffitt et al., US20060259107 entitled: SYSTEM FOR SELECTIVE    ACTIVATION OF A NERVE TRUNK USING A TRANSVASCULAR RESHAPING LEAD;-   Denker et al. U.S. Pat. No. 6,907,285 entitled: IMPLANTABLE    DEFIBRILLATOR WITH WIRELESS VASCULAR STENT ELECTRODES;-   Chavan et al. US20070093875 entitled IMPLANTABLE AND RECHARGEABLE    NEURAL STIMULATOR;-   Rezai, U.S. Pat. No. 6,885,888 entitled ELECTRICAL STIMULATION OF    THE SYMPATHETIC NERVE CHAIN;-   Mehra, U.S. Pat. No. 5,170,802 entitled IMPLANTABLE ELECTRODE FOR    LOCATION WITHIN A BLOOD VESSEL;-   Mahchek et al. U.S. Pat. No. 5,954,761 entitled: IMPLANTABLE    ENDOCARDIAL LEAD ASSEMBLY HAVING A STENT;-   Webster Jr. et al. U.S. Pat. No. 6,292,695 entitled: METHOD AND    APPARATUS FOR TRANSVASCULAR TREATMENT OF TACHYCARDIA AND    FIBRILLATION;-   Stokes, U.S. Pat. No. 4,643,201;-   Ela Medical SA, EP 0993840A, U.S. Pat. No. 6,385,492-   WO 9407564 describes stent-type electrodes that can be inserted    through a patient's vasculature.-   WO 9964105A1 describes transvascular treatment of tachycarida.-   WO 9965561 A1 describes a method and apparatus for transvascular    treatment of tachycardia and fibrillation.-   WO02058785A1 entitled VASCULAR SLEEVE FOR INTRAVASCULAR NERVE    STIMULATION AND LIQUID INFUSION describes a sleeve that includes an    electrode for stimulating nerves.-   WO 06115877A1 describes vagal nerve stimulation using vascular    implanted devices.-   WO 07053508A1 entitled INTRAVASCULAR ELECTRONICS CARRIER AND    ELECTRODE FOR A TRANSVASCULAR TISSUE STIMULATION SYSTEM and    US2007/0106357A1 describe an intravascular mesh type electrode    carrier in which the conductor of a lead is interwoven into the    carrier mesh.-   U.S. Pat. No. 5,224,491 describes implantable electrodes for use in    blood vessels.-   U.S. Pat. No. 5,954,761 describes an implantable lead carrying a    stent that can be inserted into the coronary sinus.-   U.S. Pat. No. 6,006,134 describes transvenous stimulation of nerves    during open heart surgery.-   U.S. Pat. No. 6,136,021 describes an expandable electrode for    coronary venous leads (the electrode can be placed or retained in    the vasculature of the heart).-   Spreigl et al. U.S. Pat. No. 6,161,029 entitled: APPARATUS AND    METHOD FOR FIXING ELECTRODES IN A BLOOD VESSEL describes fixing    electrodes in blood vessels.-   U.S. Pat. No. 6,438,427 describes electrodes for insertion into the    coronary sinus.-   U.S. Pat. No. 6,584,362 describes leads for pacing and/or sensing    the heart from within the coronary veins.-   U.S. Pat. No. 6,778,854 describes use of electrodes in the Jugular    vein for stimulation of the Vagus nerve.-   U.S. Pat. No. 6,934,583 discloses stimulation of the Vagus nerve    with an electrode in a blood vessel.-   U.S. Pat. No. 7,072,720 describes catheter and tube electrode    devices that incorporate expanding electrodes intended to contact    the interior walls of blood vessels or anatomic structures in which    the electrode devices are implanted as well as methods involving    stimulation of the vagus nerve.-   U.S. Pat. No. 7,184,829 discloses transvascular stimulation of a    vagal nerve.-   U.S. Pat. No. 7,225,019 discloses intravascular nerve stimulation    electrodes that may be used in the Jugular vein.-   U.S. Pat. No. 7,231,260 describes intravascular electrodes.-   Schauerte et al., US 2002/0026228 entitled: ELECTRODE FOR    INTRAVASCULAR STIMULATION, CARDIOVERSION AND/OR DEFIBRILLATION;-   Jonkman et al., U.S. Pat. No. 6,006,134-   Bonner et al., U.S. Pat. No. 6,201,994-   Brownlee et al., U.S. Pat. No. 6,157,862-   Scheiner et al., U.S. Pat. No. 6,584,362-   Psukas, WO 01/00273-   FR 2801509, US 2002065544-   Morgan, U.S. Pat. No. 6,295,475-   Bulkes et al., U.S. Pat. No. 6,445,953-   Rasor et al. U.S. Pat. No. 3,835,864 entitled: INTRA-CARDIAC    STIMULATOR-   Denker et al. US20050187584-   Denker et al. US2006/0074449A1 entitled: INTRAVASCULAR STIMULATION    SYSTEM WITH WIRELESS POWER SUPPLY;-   Denker et al. US2007/0106357A1 entitled: INTRAVASCULAR ELECTRONICS    CARRIER ELECTRODE FOR A TRANSVASCULAR TISSUE STIMULATION SYSTEM;-   Boveja et al. US20050143787-   Transvenous Parassympathetic cardiac nerve stimulation; an approach    for stable sinus rate control, Journal of Cardiovascular    Electrophysiology 10(11) pp. 1517-1524 November 1999-   Transvenous Parassympathetic nerve stimulation in the inferior vena    cava and atrioventricular conduction, Journal of Cardiovascular    Electrophysiology 11(1) pp. 64-69, January 2000.-   Planas et al., Diaphragmatic pressures: transvenous vs. direct    phrenic nerve stimulation, J. Appl. Physiol. 59(1): 269-273, 1985.-   Yelena Nabutovsky, M. S. et al., Lead Design and Initial    Applications of a New Lead for Long-Term Endovascular Vagal    Stimulation, PACE vol. 30, Supplement 1, January 2007 p. S215

Other references of interest include:

-   Amundson, U.S. Pat. No. 5,779,732

There remains a need for surgically simpler, cost-effective andpractical apparatus and methods for nerve stimulation.

SUMMARY OF THE INVENTION

This invention has a range of aspects. One aspect of the inventionprovides electrodes for transvascular stimulation of nerves. Inembodiments, electrode structures comprise at least one electrodesupported on an electrically-insulating backing sheet; and, a structurefor holding the backing sheet against the inner wall of a blood vesselwith the electrode in contact with the inner wall of the blood vessel.In some embodiments, the backing sheet is designed to unroll inside thelumen of a blood vessel to fit around the periphery of the lumen of ablood vessel. In such embodiments, the backing sheet can comprise thestructure for holding the backing sheet against the inner wall of theblood vessel. In other embodiments an expandable stent or a tube isprovided to hold the backing sheet and electrodes against the bloodvessel wall.

Another aspect of the invention comprises a nerve stimulation systemcomprising a stimulation signal generator and first and second electrodestructures. The first electrode structure comprises a first plurality ofelectrodes and is dimensioned to be implantable at a position along alumen of a person's left subclavian vein that is proximate to the leftphrenic nerve. The second electrode structure comprises a secondplurality of electrodes and is dimensioned to be implantable at aposition along a lumen of the person's superior vena cava that isproximate to the right phrenic nerve. The system comprises means such aselectrical leads, a wireless system or the like for transmitting signalsfrom the signal generator to the first and second pluralities ofelectrodes.

Another aspect of the invention provides a method for regulatingbreathing of a person. The method comprises implanting at least one of:a first electrode structure at a position along a lumen of the leftsubclavian vein that is proximate to the left phrenic nerve; and asecond electrode structure at a position along a lumen of the superiorvena cava that is proximate to the right phrenic nerve; and subsequentlystimulating the left- and right-phrenic nerves by applying stimulationsignals to electrodes of the first and second electrode structures.

Further aspects of the invention and features of specific exampleembodiments of the invention are described below.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate non-limiting example embodiments ofthe invention.

FIG. 1 shows a number of nerves adjacent to a blood vessel.

FIG. 2 is a schematic diagram of a transvascular nerve stimulationapparatus according to an example embodiment.

FIG. 3 is a cross section through an electrode structure having multipleelectrodes or rows of electrodes spaced apart around an inner wall of ablood vessel.

FIGS. 4A, 4B and 4C are partially schematic cross sectional viewsillustrating stages in the implanting of an electrode structureaccording to an example embodiment which includes an expandable stent ina blood vessel.

FIGS. 5A, 5B and 5C are partially schematic cross sectional viewsillustrating an electrode structure according to an embodiment having anengagement structure for holding the electrode structure expandedagainst an inner wall of a blood vessel.

FIGS. 6 and 6A are respectively perspective and cross sectional viewsshowing an electrode structure according to another embodiment whereinelectrodes are held against an inner wall of a blood vessel by aretention tube.

FIGS. 7A and 7B are perspective views showing an electrode structurehaving four electrodes respectively in a flat configuration and a rolledconfiguration. In the rolled configuration, the electrodes face radiallyoutward.

FIGS. 7C and 7F are views showing plan views of unrolled electrodestructures having electrodes that may be used in bipolar pairs (amongother electrical configurations). FIGS. 7D and 7E show example ways forpairing the electrodes of the electrode structure of FIG. 7C.

FIG. 7G is a perspective view showing an electrode structure having fourrows of electrodes in a rolled configuration in which the electrodestructure is curled up within an apertured insertion tube.

FIG. 7H is a cross section through a blood vessel within which anelectrode structure according to another embodiment has been placed.

FIGS. 8A and 8B are schematic illustrations of the use of a structurecomprising bi-polar electrodes to stimulate a nerve extendingtransversely to a blood vessel.

FIG. 8C is a schematic illustrations of the use of a structurecomprising bi-polar electrodes to stimulate a nerve extending generallyparallel to a blood vessel.

FIG. 9 is a cut away view of a person's neck.

FIG. 9A is a cut away view illustrating a minimally invasivetransvascular nerve stimulation system installed in a person accordingto an embodiment wherein an electrode structure is disposed in theperson's internal jugular vein in the neck or upper chest region.

FIGS. 10A and 10B illustrate the anatomy of selected nerves and bloodvessels in a person's neck and upper torso.

FIG. 11 is a cut away view illustrating a minimally invasivetransvascular nerve stimulation system installed in a person accordingto an embodiment wherein electrode structures are disposed in one orboth of the person's superior vena cava and left subclavian vein.

FIG. 12 is a cut away view illustrating a minimally invasivetransvascular nerve stimulation system installed in a person accordingto an embodiment wherein control signals are transmitted wirelessly tocause stimulation signals to be delivered at electrode structures.

DESCRIPTION

Throughout the following description, specific details are set forth inorder to provide a more thorough understanding of the invention.However, the invention may be practiced without these particulars. Inother instances, well known elements have not been shown or described indetail to avoid unnecessarily obscuring the invention. Accordingly, thespecification and drawings are to be regarded in an illustrative, ratherthan a restrictive, sense.

This invention relates to transvascular stimulation of nerves. Intransvascular stimulation, suitable arrangements of one or moreelectrodes are positioned in a blood vessel that passes close to a nerveto be stimulated. Electrical currents pass from the electrodes through awall of the blood vessel to stimulate the nerve.

FIG. 1 shows three nerves, N1, N2 and N3 that pass nearby a blood vesselV having a wall W defining a lumen L. FIG. 1 is illustrative and notintended to represent any specific blood vessel or nerves. FIG. 1represents any suitable one of the various places in the body wherenerves pass nearby to veins or arteries. Nerves N1 and N2 extend roughlyparallel to blood vessel V and nerve N3 extends generally transverselyto blood vessel V, at least in their parts depicted in FIG. 1. Nerve N1is closer to blood vessel V than nerve N2.

FIG. 2 illustrates schematically the use of an electrode structure 10inserted into lumen L of blood vessel V to stimulate nerve N1. Electrodestructure 10 comprises an electrode 12, an electrically-insulatingbacking layer 14 and a means 15 for holding electrode 12 and backinglayer 14 in place against the inner wall of blood vessel V. Electrode 12may be attached to backing layer 14. This is not mandatory, however. Itis sufficient that electrode 12 can be held against or at least in closeproximity to the wall W of the blood vessel and that backing layer 14covers the side of electrode 12 facing into lumen L. Various examplestructures that may be used as means 15 are described below. Electrodestructures which provide electrodes backed by electrically-insulatingbarriers as illustrated generally in FIG. 2 may be provided in a varietyof ways.

Electrode 12 is connected to a signal generator 18 by a suitable lead17. Signal generator 18 supplies electrical current to electrode 12 byway of lead 17. Signal generator 18 may be implanted or external to thebody. Signal generator 18 may, for example, comprise an implantablepulse generator (IPG).

In some embodiments electrode structure 10 includes a circuit (notshown) for applying signals to one or more electrodes 12 and a battery,system for receiving power wirelessly or another supply of electricalpower. In such embodiments, signal generator 18 may deliver controlsignals which cause the circuit to apply stimulation signals toelectrode 12 by way of a suitable wireless link technology. The wirelesslink may provide communication of the control signals between a smalltransmitter associated with signal generator 18 and a small receiverassociated with electrode structure 10. With suitably miniaturecircuitry, it may be possible to provide a signal generator 18 that isco-located in a sufficiently large blood vessel with electrode structure10. The signal generator 18 may, for example, comprise a thin electroniccircuit embedded within backing sheet 14.

Electrode 12 serves as a source or as a sink for electrical current.Depending upon the nature of the electrical signals generated by signalgenerator 18 electrode 12 may serve as a current source at some timesand as a current sink at other times. Another electrode or group ofelectrodes (not shown in FIG. 2) in contact with the patient serves tocomplete an electrical circuit. The other electrode or group ofelectrodes may be incorporated in electrode structure 10 (as is usuallypreferable) or may be separate.

Electrically-insulating backing layer 14 presents a high-impedance tothe flow of electrical current and therefore reduces the amount ofcurrent flow through the blood in blood vessel V. It is not mandatorythat layer 14 have an extremely high electrical resistance. It issufficient if layer 14 has a resistance to the flow of electricitythrough layer 14 that is significantly greater than that presented bythe blood in blood vessel V. Blood typically has a resistivity of about120 to 190 Ωcm. In example embodiments, the blood in a blood vessel mayprovide an electrical resistance between closely-spaced electricalcontacts that is inversely proportional to the dimensions of the lumenof the blood vessel. In large blood vessels the longitudinal electricalresistance between reasonable closely-spaced contacts can be a few tensof ohms for example. Layer 14 preferably provides an electricalresistance of at least a few hundred ohms, preferably a few kilo ohms ormore to the flow of electrical current through the thickness of layer14. Layer 14 could have electrically conductive members such as leadsand the like embedded within it or electrically-conductive on its innersurface and still be considered to be ‘electrically-insulating’.

By making layer 14 of a suitable material such as silicone rubberelastomer, a biocompatible plastic, or another biocompatible insulatingmaterial it is easily possible to provide a backing layer 14 having asuitable resistance to the flow of electrical current. FIG. 2illustrates how the presence of backing layer 14 directs the electricfield E (illustrated schematically in FIG. 2 by lines of equipotential)outwardly from blood vessel V.

In FIG. 2, the delivery of electrical stimulation to nerve N1 isenhanced by:

-   -   Locating electrode 12 against the internal wall of blood vessel        V at a location close to nerve N1;    -   Providing an electrode 12 having a relatively large contact        surface that can achieve a large contact area with the inner        wall of blood vessel V;    -   Curving the contact surface of electrode 12 to roughly match the        curvature of the inner face of blood vessel V;    -   Providing electrically-insulating backing sheet 14.        With these features, a significantly lower stimulation intensity        is required to stimulate target nerve N1 than would be the case        for wire electrodes located in lumen L in contact with the blood        in lumen L. Additionally, selectivity for a nerve of interest is        improved. Advantageously, electrodes 12 have active surface        areas in the range of about ½ mm² to about 5 mm². In some        embodiments, each electrode has an active surface area on the        order of 2 mm².

Electrode structure 10 may be introduced into blood vessel V in aminimally-invasive, safe way. Blood vessel V may be a relatively largeblood vessel that courses in the vicinity of the target nerve N1. Insome embodiments, electrode structure 10 comprises a flexiblemulti-contact electrode carrier sheet (ECS) of suitable dimensions. Thesheet may be tightly coiled prior to its insertion into blood vessel V.Once within blood vessel V the sheet may be allowed to unwind so as tobring electrode 12 into contact with wall W of blood vessel V.

An electrode structure may support multiple electrodes. FIG. 3 shows anexample electrode structure 20 which supports a number of electrodesincluding electrodes 22A, 22B, 22C and 22D (collectively electrodes 22).Other electrodes out of the plane of FIG. 3 may also be present. In theillustrated embodiment, electrodes 22A, 22B, 22C and 22D arecircumferentially spaced approximately equally around the perimeter ofthe inside wall of blood vessel V. Each electrode 22 is insulated fromthe lumen of blood vessel V by a thin flexible insulating sheet 24(individually identified as 24A, 24B, 24C and 24D. Each of theinsulating sheets 24 is conformally disposed against the internal wallof blood vessel V. In alternative embodiments, two or more electrodesare disposed on a common insulating sheet. Insulating sheets 24 may bejoined together or may be different parts of a continuous sheet.

E1, E2, E3 and E4 illustrate the areas corresponding to electrodes 24Athrough 24D in which the electrical field associated with current flowat the corresponding electrode is strong enough to stimulate a nerve.Increasing the strength of the signal (e.g. a stimulation pulse) at anelectrode increases the affected area (as indicated by the larger dottedregions).

FIG. 3 shows two nerves N4 and N5. It can be seen that a stimulationsignal from electrode 22A can stimulate nerve N4. A stimulation signalfrom electrode 22B can stimulate nerve N5. The arrangement of bloodvessel V and nerves N4 and N5 is like the arrangement of the internaljugular vein and the phrenic and vagus nerves in the neck region of aperson. With an arrangement as shown in FIG. 3, a target phrenic nerveat the location of N4 can be preferentially stimulated by electrode 22Adue to greater proximity of electrode 22A and also due to the shape ofthe area E1 affected by electrode 22A. The vagus nerve at location N5 isusually approximately diametrically opposite from electrode 22A and isnot affected by signals delivered at normal levels at electrode 22A. Thevagus nerve is, however, affected by signals delivered at electrode 22C.

The phrenic nerve and vagus nerve in adult humans are each typicallyabout 2 mm in diameter. The lumen of the internal jugular vein in adulthumans is typically in the range of about 10 mm to 20 mm in diameter.The distance from the phrenic nerve to the internal jugular vein and thedistance from the vagus nerve to the internal jugular vein are eachtypically in the range of about 2 mm to about 10 mm. Generally thephrenic nerve and vagus nerve are on opposite sides of the internaljugular vein so that they are roughly 15 mm to 30 mm apart from oneanother. This arrangement facilitates the ability to performtransvascular stimulation of only the vagus nerve or only the phrenicnerve without stimulating the other nerve. A system according to someembodiments stimulates the phrenic nerve or vagus nerve only. A systemaccording to other embodiments selectively stimulates either or both ofthe phrenic and vagus nerves from an electrode structure located in theinternal jugular vein.

In many cases, nerves comprise a plurality of fascicles. For example, inthe example illustrated in FIG. 3, the phrenic nerve N4 is composed ofthree phrenic fascicles PF1, PF2, and PF3. These phrenic fascicles maybe selectively recruited by progressive levels of stimulation current atelectrode 22A. At lower stimulation levels, only PF1 is recruited. Athigher levels PF1 and PF2 are both recruited. At still higher levels,all of PF1, PF2 and PF3 are recruited. In FIG. 3, the vagus nerve N5 iscomposed of two vagus fascicles VF1, and VF2 that may be selectivelyrecruited by progressive levels of stimulation current at electrode 22C.At lower stimulation levels only VF1 is recruited. At higher stimulationlevels both VF1 and VF2 are recruited.

It is desirable that an electrode structure provide a minimumobstruction to the flow of blood in lumen L of a blood vessel V.Therefore, electrode structures are preferably thin in comparison to theinner diameter of blood vessel V. In some embodiments, a structure thatsupports electrodes and insulating backing sheets gently urges theelectrodes and insulating backing sheets radially outward in lumen L soas to leave an open passage for blood flow past the electrode structure.To prevent the disruption or blockage of blood flow in a blood vessel,the cross-sectional area of an intravascular electrode structure shouldnot exceed a certain fraction of the cross-sectional area of the lumenof the blood vessel. A round blood vessel with an internal diameter of10 mm has a cross-sectional area of approximately 75 mm². Thecircumference of the electrode structure when expanded in the bloodvessel should preferably not be greater than about 10×π mm,(approximately 30 mm). If the thickness of an electrode structure isbetween about 0.3 and 0.5 mm then the cross-sectional area of theelectrode structure will be about 10 mm² to 15 mm², which representsless than 20% of the lumen of the vessel.

FIGS. 4A, 4B and 4C show an electrode structure 30 according to anexample embodiment. Electrode structure 30 comprises a plurality ofelectrodes 32 disposed on a flexible electrically-insulating sheet 34.Electrode structure is initially introduced into a blood vessel Vtightly curled up around an expandable stent 35 inside an introducertube 36. Stent 35 may, for example, comprise an expandable wire stent. Avariety of suitable expandable wire stents is available from medicaldevices manufacturers.

Electrode structure 30 is guided to a desired location in a blood vesselV inside introducer tube 36. At the desired location, introducer tube 36is retracted to allow electrically-insulating sheet 34 to begin tounroll as shown in FIG. 4B. Stent 35 is then expanded in order tofurther unroll electrically-insulating sheet 34 and to urge electricallyinsulating sheet 34 and the electrodes 32 carried onelectrically-insulating sheet 34 against the inner wall of blood vesselV as shown in FIG. 4C.

In the illustrated embodiment, stent 35 is attached to sheet 34 at apoint, row of points or line 37. Stent 35 is left in place to retainelectrodes 32 and sheet 34.

Stent 35 may comprise any suitable type of expandable stent. A widerange of such stents are known. Stent 35 is expanded in a mannerappropriate to the stent. For example, in some embodiments a balloon isplaced inside the stent and the stent is expanded by inflating theballoon. The balloon may be withdrawn after the stent has been expanded.

FIGS. 5A, 5B and 5C illustrate an electrode structure 40 which issimilar to electrode structure 30 except that it has electrodes 42supported on a flexible sheet 44 and an engagement mechanism 47 whichallows opposed edges portions 44A and 44B of flexible sheet 44 to belocked together when flexible sheet 44 has been opened within the lumenL of blood vessel V. The locking together of edge portions 44A and 44Bholds flexible sheet 44 in an expanded configuration with electrodes 42contacting the inner surface of wall W. Electrode structure 40 does nothave a stent inside flexible sheet 44 (although a stent could optionallybe added to provide further support for sheet 44). Sheet 44 may be madeso that it has a tendency to unroll toward a configuration that is lesstightly-rolled than shown in either of FIG. 5A or 5B. This tendency willbias sheet 44 to open into the configuration of FIG. 5B when removedfrom insertion tube 46 and will help to hold sheet 44 in place insideblood vessel V.

In the illustrated embodiment, mechanism 47 comprises mating sets ofridges 47A and 47B that extend longitudinally respectively along edgeportions 44A and 44B. Ridges 47A and 47B are on opposing major surfacesof sheet 44 so that they can contact one another when sheet 44 issufficiently unrolled. As shown in FIG. 5B, ridges 47A and 47B interlockwhen sheet 44 is unrolled as fully as the dimension of blood vessel Vwill permit. Mechanism 47 thus serves to retain sheet 44 and electrodes42 snugly against the inside of wall W and prevent sheet 44 from curlinginwardly or moving away from the wall W.

In preferred embodiments, mechanism 47 permits engagement of edgeportions 44A and 44B in a range of degrees of overlap. Thus, mechanism47 allows engagement of edge portions 44A and 44B when sheet 44 has beenexpanded against the inner wall of blood vessels having sizes within agiven range of different sizes.

Alternative engagement mechanisms 47 are possible. For example, in someembodiments, a biocompatible adhesive is introduced between edgeportions 44A and 44B. In other embodiments, ridges or other interlockingfeatures and a biocompatible glue are both used.

An electrode structure 40 may be placed in a desired location by:introducing and sliding the electrode structure along a blood vessel toa desired location; at the desired location, sliding electrode structure40 out of tube 46; if electrode structure 40 is partially or entirelyself-unwinding, allowing electrode structure 40 to unwind; and, ifnecessary, inflating a balloon 49 to fully expand electrode structure 40and/or engage engagement mechanism 47. Introducing the electrodestructure may comprise cannulating the blood vessel and introducing theelectrode structure at the cannulation site.

FIG. 5C illustrates a method for removing or relocating an electrodestructure 40. Electrode structure 40 comprises a tab 48 or otherprojection that is attached to sheet 44 near or at an inside edgethereof and is graspable from within lumen L. A tool 50 is inserted intolumen L and has jaws 51 operable to grasp tab 48. At position 50A jaws51 of tool 50 are opened to receive tab 48. At position 50B, jaws 51have been operated to grasp tab 48. At position 50C tool 50 has beenmoved toward the center of lumen L and tool 50 has thereby peeled theinner edge of sheet 44 away from wall W. Tool 50 may be rotated aboutits axis to roll electrode structure 40 into a smaller configuration.Electrode structure 40 may then be moved along blood vessel 44 to a newposition; or pulled into an insertion tube for safe removal from bloodvessel V.

FIGS. 6 and 6A show an electrode structure 70 that includes a rolled,flexible electrically-insulating sheet 74 carrying electrodes 72. Sheet74 may be opened by partial unrolling within a blood vessel V. A tubularretainer 73 may then be inserted to retain sheet 74 and electrodes 72 inplace against a wall of the blood vessel. In cases where electrodestructure 70 is to be inserted into the blood vessel through an incisionthat is smaller than the lumen of the blood vessel then tubular retainer73 may be expandable so that it can be introduced through the openingand then expanded to a size suitable for retaining sheet 74 andelectrodes 72.

Retainer 73 has a diameter selected such that, when placed inside sheet74, it will retain sheet 74 and electrodes 72 in close apposition to theinside wall of the blood vessel for as long as required. The outsidediameter of retainer 73 is chosen to closely match the inner diameter ofthe blood vessel V minus twice the thickness of sheet 74. For example,for a blood vessel with an inside diameter of 10 mm and an electrodestructure 70 with sheet thickness of ½ mm, the outside diameter ofretainer 73 should be approximately 10 mm−2×½ mm=9 mm. Retainers 73 in arange of diameters may be provided to allow a surgeon to select andinsert the best size. In typical blood vessels having inner diameters of10 mm or more, the length of retainer 73 should be at least about twiceits diameter to ensure that retainer 73 will not tilt inside the bloodvessel. The wall thickness of retainer 73 may be fairly small, forexample, up to about 0.3 mm or so. Retainer 73 may be made of a suitablematerial such as a biocompatible metal (e.g. stainless steel ortitanium) or a high-strength biocompatible polymer.

Wires 75 carry signals from a signal generator to electrodes 72. In analternative embodiment, a signal generator is integrated with electrodestructure 70. Such as signal generator may be controlled to issuestimulation pulses in response to control signals provided by way of asuitable wireless link.

FIGS. 7A to 7G show examples of electrode structures. Electrodestructure 80 of FIG. 7A has four electrodes 82 (individually 82A to 82D)supported on a major face 81 of a flexible insulating sheet 84.Insulated leads 85 connect electrodes 82 to a signal generator (notshown in FIG. 7A). Sheet 84 may comprise a flexible layer of siliconefor example. Electrodes 82 and electrode leads 85 may be of any suitableshape and material; e.g., stainless steel or platinum-iridiummulti-stranded wire electrodes with Teflon™ coated wire leads.

An electrode structure 80 may be fabricated, for example, by connectingsuitable electrodes to coated wire leads and then embedding theelectrodes and leads in a layer of silicone such that the electrodes areexposed on one major face of the silicone layer but not the other.

Electrode structure 80 may be used to stimulate nerves by insertingelectrode structure 80 into a blood vessel with electrodes 82 facingoutwardly; and connecting any one electrode to the negative output of astandard constant-current (preferably) or constant-voltage nervestimulator (cathodic stimulation) with respect to a remote referenceelectrode. Alternatively, any two electrodes 82 can be selected as anodeand cathode.

Electrode structure 80 is similar to a nerve cuff but ‘inside out’. Eachelectrode preferentially stimulates a sector of tissue that radiatesoutwardly from a blood vessel V and spans a limited angle. For example,in an electrode structure having four electrodes disposed approximatelyevery 90 degrees around the circumference of a blood vessel, the volumeof tissue affected by each electrode may span approximately 90 degrees(see FIG. 3 for example).

A further improvement in angular selectivity may be obtained byproviding longitudinal ridges on the outer major surface of electrodestructure 80. The ridges enhance the electrical separation betweencircumferentially-adjacent electrodes 82. The ridges may be similar tothe ridges described in Hoffer et al. U.S. Pat. No. 5,824,027 entitledNERVE CUFF HAVING ONE OR MORE ISOLATED CHAMBERS which is herebyincorporated herein by reference. Ridges 86 are shown schematically inFIG. 7A.

Optionally, sheet 84 may include geometrical complexities such as holesor protuberances to provide a better substrate for connective tissueadhesion and so increase the long-term mechanical stability andimmobility of structure 80 inside a blood vessel.

FIG. 7B shows an electrode structure like electrode structure 80 wrappedinto a tight spiral with electrodes facing out in preparation forinsertion into a blood vessel.

FIG. 7C shows an electrode structure 90 according to another embodiment.Electrode structure 90 comprises a flexible sheet 94 that supports fourpairs of electrodes 92. Sheet 94 may comprise a thin flexible siliconesheet, for example. Electrical leads 93 are provided to connectcorresponding electrodes 92 to a signal source. Electrodes and electrodeleads may be of any suitable shape and material; e.g., stainless steelor platinum-iridium multi-stranded wire with Teflon™ coated leads. Inthe illustrated embodiment, electrode contact surfaces are exposedthrough electrode windows in which insulation of the leads is notpresent. Electrodes 92A and 92E; 92B and 92F; 92C and 92G; and 92D and92H may be paired, for example, as shown in FIG. 7D. As another example,electrodes 92A and 92B; 92C and 92D; 92E and 92F; and 92G and 92H may bepaired as shown in FIG. 7E.

Electrode structure 90 may be applied to stimulate a nerve or nerves byinserting electrode structure 90 into a blood vessel with electrodes 92facing outwardly; and connecting any two electrodes 92 to the negativeand positive outputs of a standard constant-current or constant-voltagenerve stimulator. An effective mode of stimulation is to select a pairof electrodes that are aligned along a line that is generally parallelto the target nerve, such that the greatest potential difference duringstimulation will be generated along the nerve axons in the target nerve.Since the target nerve and target blood vessel may not be strictlyparallel to one another, it is useful to have multiple electrodes in anelectrode structure from which the pair of electrodes that provide thegreatest stimulation selectivity for a target nerve can be identified bytrial and error.

FIG. 7F shows an electrode structure 90A that is like electrodestructure 90 except that it includes ridges 91 ofelectrically-insulating material that extend between groups ofelectrodes 92.

FIG. 7G shows an electrode structure like electrode structure 90prepared for insertion into a blood vessel. Electrode structure 90 isrolled up into a spiral and held by an outside retainer 95. Outsideretainer 95 has relatively thin walls. For example, the wall thicknessmay be about ½ mm or less in some embodiments. Apertures 96 penetratethe wall of outside retainer 95 and allow flow of electrical currents.Apertures 96 could optionally be filled with electrically-conductingplugs.

At least one electrode 92 of electrode structure 90 is electricallyexposed to the surroundings through an aperture 96. As the electrodestructure is being advanced toward an intravascular target location (thetarget location may be determined in advance from an imaging surveystudy for each patient, and monitored with fluoroscopy during the ECSimplant procedure), electrodes 92 are energized. Since at least someelectrodes 92 are exposed by way of apertures 96 the target nerve willbe stimulated when electrode structure 90 is close enough to the targetnerve. An effect of stimulation of the target nerve can be watched forin order to determine when electrode structure has reached the vicinityof the target nerve. The response may be monitored to fine tune theposition of electrode structure 90 in a blood vessel. Outside retainer95 may be removed when electrode structure 90 is at the target location.Outside retainer 95 is tethered by a tether 97 so that it can berecovered after deployment of structure 90.

FIG. 7H shows structure 90 at its intended location in blood vessel V.Outer retainer 96 has been removed and the structure 90 has been allowedto unwind and deploy against the inside wall of blood vessel V. Thewidth (circumferential dimension) of structure 90 is chosen to closelymatch the inside perimeter of blood vessel V at the target location. Theinside dimension of the blood vessel V may have been previouslydetermined from ultrasound imaging, balloon catheter, magnetic resonanceimaging or other non-invasive or minimally-invasive imaging technique.

When electrode structure 90 is at its desired position for optimalstimulation of the target nerve, the outer retainer 95 is gently removedand withdrawn from the patient's body while structure 90 is kept inplace, if needed, by means of a semi-rigid rod-like tool (not shown)that is temporarily used to stabilize structure 90 and prevent it frommoving while outer retainer 95 is withdrawn. As the outer retainer 95 iswithdrawn, structure 90 will naturally and rapidly unwrap toward itspreferred enlarged-cylindrical (or near-planar in some embodiments)configuration and will stretch out against the inside wall of the bloodvessel with electrodes 92 disposed outwardly in close contact to theblood vessel wall.

As noted above, the choice of electrodes to use to stimulate a targetnerve can depend on the orientation of the target nerve relative to theblood vessel in which an electrode structure is deployed. Where a targetnerve passes more or less at right angles to a blood vessel, it can bemost efficient to stimulate the target nerve by passing electric currentbetween two electrodes that are spaced apart circumferentially aroundthe wall of the blood vessel. In such cases it may be desirable toprovide elongated electrodes that extend generally parallel to the bloodvessel (e.g. generally parallel to an axis of curvature of the electrodestructure). Such elongated electrodes may be emulated by a row ofsmaller electrodes that are electrically connected together.

FIGS. 8A and 8B show a nerve N extending transversely to a blood vesselV. In the illustrated embodiment, the nerve extends generally at rightangles to the blood vessel. An electrode structure 54 comprising firstand second electrodes 55A and 55B (collectively electrodes 55) islocated in lumen L of blood vessel V. Electrodes 55 are each close to orpressed against the inner face of wall W of blood vessel V. Electrodestructure 54 may have additional electrodes as well as other featuressuch as a structure for holding electrodes 54 in place however these arenot shown in FIG. 8A or 8B for clarity. Electrodes 55A and 55B arespaced apart from one another in a circumferential direction around theperiphery of blood vessel V. Electrodes 55 are ideally disposed in aplane in which nerve N lies and which intersects blood vessel Vperpendicularly. Precise placement of the electrodes in such aconfiguration is not mandatory. Electrodes 55 are spaced apart in adirection that is generally along an axis of nerve N.

Each electrode 55 is protected against electrical contact with the bloodin lumen L of blood vessel V by an insulating backing member 56. In theillustrated embodiment, backing members 56 comprise hollow insulatingcaps that may, for example, have the form of hollow hemispheres. An edgeof each insulating cap contacts wall W of blood vessel V around theperiphery of the corresponding electrode 55.

In this embodiment, electrodes 55 are connected in a bi-polararrangement such that one electrode acts as a current source and theother acts as a current sink. It is not mandatory that the polarities ofelectrodes 55 always stay the same. For example, in some stimulationmodes the polarities could be switched. In the illustrated embodiment,electrode 55A is connected as a cathode (negative) electrode whileelectrode 55B is connected as an anode (positive) electrode to a signalsource (not shown in FIG. 8A or 8B). When a stimulation signal isapplied between electrodes 55 an electric field is created. The electricfield causes small electrical currents to flow between electrodes 55 byway of the surrounding tissues.

Since electrodes 55 are insulated from the lumen of blood vessel V,electric current flows out of the current source electrode 55A throughwall W and surrounding tissues and returns to the current sink electrode55B. The stimulation current flows longitudinally through the nerve N inthe direction shown by arrows F. For stimulation pulses of sufficientduration and intensity, the nerve axons in target nerve N will generateaction potentials that will be conducted along the stimulated axons innerve N.

Where a target nerve extends generally parallel to a blood vessel it canbe efficient to stimulate the target nerve by passing electric currentbetween two electrodes that are spaced apart longitudinally along thewall of the blood vessel.

FIG. 8C shows a nerve N extending parallel to a blood vessel V. Anelectrode structure 88 having first and second electrodes 89A and 89B(collectively electrodes 89) is located inside blood vessel V withelectrodes 89A and 89B close to, preferably against the inside of thewall W of blood vessel V. Electrode structure 88 may have additionalelectrodes as well as other features such as a structure for holdingelectrodes 89 in place however these are not shown in FIG. 8C forclarity. Electrodes 89A and 89B are spaced apart from one another in alongitudinal direction along blood vessel V. The electrodes are ideallydisposed on a line extending parallel to an axis of the blood vesselalthough precise placement of the electrodes in such a configuration isnot mandatory.

In this embodiment, electrodes 89A and 89B are connected in a bi-polararrangement such that one electrode acts as a current source and theother acts as a current sink. It is not mandatory that the polarities ofelectrodes 89A and 89B always stay the same. For example, in somestimulation modes the polarities could be switched.

In the illustrated embodiment, electrode 89A is connected as a cathode(negative) electrode while electrode 89B is connected as an anode(positive) electrode to a signal source (not shown in FIG. 8C). Eachelectrode 89 is protected against electrical contact with the blood inlumen L of blood vessel V by an insulating backing member 87. In theillustrated embodiment, the backing members comprise hollow insulatingcaps that may, for example, have the form of hollow hemispheres. An edgeof each insulating cap contacts the wall of blood vessel V around theperiphery of the corresponding electrode 89.

Since electrodes 89 are electrically insulated from the blood in lumen Lof blood vessel V, electric current flows out of the current source(e.g. cathode 89A), through wall W and eventually returns to the currentsink (e.g. anode electrode 89B). This results in a stimulation currentthat flows longitudinally through nerve N in the direction shown byarrows F. For stimulation pulses of sufficient duration and intensity,the nerve axons in the target nerve will generate action potentials thatwill be conducted along the stimulated axons in nerve N.

Stimulating the phrenic nerves to regulate or cause breathing is anexample application of electrode structures as described herein. Thepresent invention provides a surgically simple, lower risk response tothe need of stimulating the phrenic nerves to control the movement ofthe diaphragm and restore normal breathing rate in people who have lostcontrol of diaphragm due to a central neurological lesion such as a highcervical spinal cord injury or disease, including quadriplegia; centralalveolar hypoventilation; decreased day or night ventilatory drive (e.g.central sleep apnea, Ondine's Curse) or brain stem injury or disease.Phrenic nerves may be stimulated on an acute care or chronic basis.

The phrenic nerves provide the major nerve supply to the diaphragm. Eachphrenic nerve contributes predominantly motor fibres solely to itshemidiaphragm. The passage taken by the right and left phrenic nervesthrough the thorax is different. This is largely due to the dispositionof great vessels within the mediastinum. Occasionally, the phrenic nervemay be joined by an accessory phrenic nerve.

The phrenic nerve on both sides originates from the ventral rami of thethird to fifth cervical nerves. The phrenic nerve passes inferiorly downthe neck to the lateral border of scalenus anterior. Then, it passesmedially across the border of scalenus anterior parallel to the internaljugular vein which lies inferomedially. At this point the phrenic nerveis deep to the prevertebral fascia, the transverse cervical artery andthe suprascapular artery.

At the anterior, inferomedial margin of scalenus anterior and hencesuperficial to the second part of the right subclavian artery, the rightphrenic nerve passes medially to cross the pleural cupola deep to thesubclavian vein. More medially, it crosses the internal thoracic arteryat approximately the level of the first costochondral junction.

Within the thorax the right phrenic nerve is in contact with mediastinalpleura laterally and medially, in succession from superior to inferior,the following venous structures: right brachiocephalic vein, superiorvena cava, pericardium of the right atrium, inferior vena cava. From thelevel of the superior vena cava it is joined by the pericardiophrenicartery and both run inferiorly anterior to the lung root. The rightphrenic nerve pierces the diaphragm in its tendinous portion justslightly lateral to the inferior vena caval foramen. It then forms threebranches on the inferior surface of the diaphragm: anterior, lateral andposterior. These ramify out in a radial manner from the point ofperforation to supply all but the periphery of the muscle.

At the anteroinferior medial margin of scalenus anterior, the leftphrenic nerve crosses the first part of the left subclavian artery andthen the internal thoracic artery sited slightly inferiorly. Passinginferiorly with the internal thoracic artery laterally, it lies deep tothe left brachiocephalic vein and the left first costochondral joint. Itreceives a pericardiophrenic branch of the internal thoracic arterywhich stays with its distal course.

Within the thorax, the left phrenic nerve continues inferiorly andslightly laterally on the anterolateral aspect of the arch of the aorta,separated from the posterior right vagus nerve by the left superiorintercostal vein. Then it descends anterior to the root of the left lungintermediate to fibrous pericardium medially and parietal pleuralaterally. Finally, it curves inferiorly and anteriorly to reach thesurface of the diaphragm which it pierces anterior to the central tendonand lateral to the pericardium. It then forms three branches on theinferior surface of the diaphragm: anterior, lateral and posterior.These ramify out in a radial manner from the point of perforation tosupply all but the periphery of the muscle.

The accessory phrenic nerve on each side occurs in roughly 15-25% ofpeople. It originates as a branch of the fifth cervical nerve whichwould otherwise pass to the subclavius. The accessory phrenic nervebegins lateral to the phrenic nerve in the neck and obliquely traversesthe anterior surface of scalenus anterior as it descends. It joins thephrenic nerve at the root of the neck to descend to the diaphragm.

FIG. 9 shows the anatomy of the neck and, in particular, the relativelocations of phrenic nerve (PhN), vagus nerve (VN) and internal jugularvein (IJV). Note that the IJV courses between the PhN and VN. The PhNmerges with the IJV and the three structures run together distally atlevel of the clavicle (indicated by circle 99).

In one example embodiment illustrated in FIG. 9A, a minimally invasivenerve stimulation system (‘MINS’) 100 comprising a flexibleintravascular electrode array 101, for example, an electrode structureof one of the embodiments described above is permanently placed inside atarget blood vessel V (in this example the left Internal Jugular Vein,IJV) in close proximity to a target nerve (in this example the leftphrenic nerve PhN). One or more electrodes of the electrode array isdisposed for selective stimulation of the PhN. Other electrodes areoptionally disposed for selective stimulation of a second target nerve,in this example the left vagus nerve VN.

The electrode leads 104 from electrode array 101 emerge from thecannulated BV at the original venous penetration site, C, and thencourse subcutaneously to connectors 105 that connect to the header of animplanted pulse generator 102 that is surgically placed in a standardsubcutaneous pocket. The pocket may be in the upper chest wall forexample. FIG. 9 shows only one electrode array 101 on the left side ofthe neck.

In this embodiment, the implanted MINS 100 stimulates the left PhN toassist breathing by causing rhythmic inspiratory movements of thediaphragm muscle (not shown in FIG. 9). Another electrode array mayadditionally be implanted in a blood vessel on the right side of thepatient's body. For example, another electrode array 101 may beimplanted in the right internal jugular vein for selective stimulationof the right PhN and, optionally, also the right VN, if so desired. Theadditional electrode array may be connected to internal pulse generator102 or to a second internal pulse generator (not shown in FIG. 9).

MINS 100 may be installed percutaneously using standard procedures forthe installation of deep catheters, cannulas, leads or otherintravascular device. Such procedures are described in the medicalliterature. Once an electrode array has been introduced to a locationnear the target location in the internal jugular vein then the positionof the electrode array may be fine-tuned by applying low-currentstimulation signals to one or more of the electrodes in electrode array101 and observing the patient's breathing.

FIGS. 10A and 10B illustrate the anatomy of the neck and chest and, inparticular, the relative locations of the left and right phrenic nerves(PhN), vagus nerves (VN), internal jugular veins (DV), brachiocephalicveins (BCV), subclavian veins (SCV) and superior vena cava (SVC). ThePhNs run approximately perpendicular to and close to the BCVs in areas107R and 107L near the IJV/BCV junctions.

Each PhN may have more that one branch. The branches may join togetherat variable locations ranging from the neck region to the chest regionbelow the IJV/BCV junctions. In the latter case, branches of the PhN oneither side of the body may course on opposite sides of the BCVs. Twobranches of the right PhN are labeled PhN-1 and PhN-2 in FIG. 10B. Theright PhN may include branches that course on either side of the SVC.The left and right PhN extend respectively to left and righthemi-diaphragms (HD).

FIG. 11 shows a MINS 110 having electrode structures 111L and 111R(collectively 111) located respectively in a patient's left SCV and SVCvessels near the left- and right-PhN respectively. Leads 112L and 112R(collectively 112) respectively connect the electrodes of left- andright-electrode structures 111L and 111R to a signal generator. In theillustrated embodiment, the signal generator comprises an implantablepulse generator (IPG) 115. Alternatively, as described above, some orall functions of pulse generator 115 may be provided by circuitry thatis co-located with or integrated with one or both of electrodestructures 111. In some embodiments, pulse generator 115 generatescontrol signals that are transmitted by way of a wireless communicationlink to cause circuitry that is local to electrode structures 111 toapply stimulation pulses by way of electrodes on electrode structures111.

The implantable pulse generator may be configured to deliver electricalpulses to electrodes of the left- and right electrode structures 111more-or-less simultaneously so that the left- and right-hemidiaphragmsare induced to undergo breathing motions in a synchronized manner. IPG115 may, for example, apply bursts of stimulus pulses at a rate of about12 or 13 bursts per minute. Each burst may, for example, comprise 20-40current pulses delivered at a rate of 20 Hz or so and last roughly 1 to2 seconds. Each burst induces signals in the phrenic nerve that causethe diaphragm to move to provide inspiration. Expiration occurs betweenbursts.

MINIS 110 can be readily installed as shown in FIG. 11. Electrodestructures 111R and 111L may both be introduced through the sameintravascular insertion point C1 in the left SCV. In some embodiments,electrode structure 111L is installed first. In such embodiments,electrode structure 111L can be passed through the left SVC pastelectrode structure 111L (e.g. through a bore of electrode structure111L) to its target location in the SVC. Flexible leadout cable 112Rpasses through electrode structure 111L. Both leadout cables 112 emergefrom the SCV and course subcutaneously to a subcutaneous pocket area inthe upper chest where the leadout cable connectors are connected to IPG115.

Locating initial target positions for electrode structures 111 isfacilitated because the SVC, heart and BCV can be readily visualizedusing available imaging techniques. It is known that the phrenic nervespass tightly past the heart on each side. Therefore, target locations inthe blood vessels within ±1 to 2 cm of the optimum positions forstimulating the phrenic nerves can be determined readily from images ofthe upper chest and lower neck.

The arrangement shown in FIG. 11 has the advantage that the distancefrom electrode structures 111 to the target nerves in these locationsmay be smaller, more uniform and more reproducible than for similarelectrodes implanted in more proximal locations in the IJV s where thetarget PhNs run parallel to the IJVs, but at more variable distances(see FIG. 9, for example).

MINS 110 may be varied by leaving out one of electrode structures 111and its associated cable 112. Such embodiments may be useful in acutecare environments where it is necessary to provide breathing assistanceusing a simple quick procedure. Such embodiments may also be useful inchronic situations where stimulation of one hemi-diaphragm issufficient. Where only one electrode structure 111 is implanted, theelectrode structure may be at either the location of electrode structure111R or the location of electrode structure 111L.

FIG. 12 shows a minimally-invasive nerve stimulation system 120 that islike MINS 110 of FIG. 11 but provides a wireless connection between animplantable pulse generator and circuits which deliver stimulationsignals to electrodes. System 120 has two sets of intravascularelectrodes 121A and 121B. In some embodiments, each set of electrodescomprises an electrode structure as described herein. Each set ofelectrodes 121A and 121B is connected by short flexible lead wires 123to an associated RF receiver unit 124. RF receiver units receivewireless stimulation commands 125 from an implanted pulse generator 126having an associated transmitter (which is built into implantable pulsegenerator 126 in the illustrated embodiment.

Each receiver unit 124 may comprise a hermetic package containing anantenna and circuitry to decode command signals and deliver stimulationpulses to the electrodes of the corresponding electrode array 121. Eachreceiver unit may be attached to an autonomous stent-like structure forsafe, permanent and stable installation in a blood vessel near theassociated electrode array 121. The receiver units may be powered by theRF signal received from implantable pulse generator 126. In such cases,the receiver units do not require internal batteries.

Implantable pulse generator 126 may contain batteries or another sourceof electrical energy, control circuitry and transmitter antennas tocommunicate with receiver units 124 and with an external programmer (notshown) that allows a therapist to program the implanted system.

In some embodiments, an implantable pulse generator or other signalsource may have a primary battery or a rechargeable battery that can beperiodically recharged through the patient's skin. In either case, it isdesirable that the battery or other source of electrical power have anexpected life span such that it will not require replacement for areasonable period such as at least about 3 to 5 years.

Methods of stimulating the phrenic nerves, as described herein can havethe advantages that:

-   -   electrodes do not come into contact with the delicate phrenic        nerves;    -   there is no implanted structure that interferes with movement of        the diaphragm;    -   the system may be implanted and self-contained such that no        wires cross the skin;    -   access to both the right and left phrenic nerves can be provided        through a single point of entry;    -   a control system, such as an implantable pulse generator may be        placed in reasonably close proximity to an electrode structure        so as to facilitate wireless control over the delivery of        stimulation pulses at the electrode structure by the implantable        pulse generator.

The applications of the apparatus and methods described herein are notlimited to phrenic and vagus nerves. The apparatus and methods describedherein may be applied to provide surgically simple, low risk solutionsfor stimulating a wide range of peripheral or cranial nerves. Forexample, the methods and apparatus may be applied to stimulate theobturator nerve in the hip/groin area or the trigeminal nerve in thehead.

The apparatus and methods may be applied to treatment of a wide varietyof disorders such as pain of peripheral or craniofacial origin, sensorydeficits, paralysis or paresis of central origin, autonomic disorders,and generally any medical condition that can be treated or alleviatedusing neuromodulation by electrical stimulation of a nerve that is inclose proximity to a larger blood vessel into which a flexiblemulti-channel electrode array can be deployed.

Advantageously, implantation of electrode structures in blood vessels isreversible and does not require surgical intervention directly involvingthe target nerves.

In some embodiments, signal generator 115 has sensors that sense acondition of the patient and adjust stimulation of the phrenic nervebased on input from the sensors. The sensors may detect things such asone or more of:

-   -   whether the patient is speaking or preparing to speak;    -   whether the patient is lying down or sitting or standing;    -   whether the patient is awake or asleep;    -   blood oxygen concentration;    -   blood CO₂ concentration;    -   etc.        In response to the sensor signals, the signal generator may        adapt the pattern or rate of breathing. For example:    -   Breathing could be automatically suppressed when a sensor signal        indicates that the patient is attempting to speak.    -   A breathing rate could be increased during periods of increased        physical activity or low blood oxygen concentration.    -   A breathing rate could be decreased or regularized during        periods of relaxation or sleep.    -   On-demand breathing stimulation could be provided in response to        the detection of the onset of irregular breathing during sleep.

The sensors may be built into the signal generator. For example, thesignal generator may include:

-   -   accelerometers and processor logic configured to determine from        outputs of the accelerometers whether the patient's motions        indicate that the patient is awake or asleep;    -   an inclinometer or accelerometer and processor logic configured        to determine from one or more outputs of the inclinometer of        accelerometer whether the patient is lying or upright.

Other sensors may be implanted. For example, in some embodiments, ablood chemistry sensor such as a blood oxygen sensor and/or a blood CO₂sensor is implanted at a suitable location in the patient. The bloodoxygen monitor may be mounted on an electrode structure 111 for example.Other sensors may sense signals in the patient's nerves.

Where a component (e.g. an electrode, signal generator, lead, stent,assembly, device, antenna, circuit, etc.) is referred to above, unlessotherwise indicated, reference to that component (including a referenceto a “means”) should be interpreted as including as equivalents of thatcomponent any component which performs the function of the describedcomponent (i.e., that is functionally equivalent), including componentswhich are not structurally equivalent to the disclosed structure whichperforms the function in the illustrated exemplary embodiments of theinvention.

As will be apparent to those skilled in the art in the light of theforegoing disclosure, many alterations and modifications are possible inthe practice of this invention without departing from the spirit orscope thereof. For example, electrodes on an electrode structure may bearranged to provide unipolar, bipolar, tripolar or balanced tripolarelectrode arrangements or combinations thereof. The example embodimentsdescribed herein include various features such as different geometriesfor insulating backing sheets, different arrangements of electrodes,different control arrangements, and the like. These features may bemixed and matched (i.e. combined on additional combinations) in otherembodiments of the invention. Accordingly, the scope of the invention isto be construed in accordance with the substance defined by thefollowing claims.

What is claimed is:
 1. A method for treating a subject, the methodcomprising: sensing an onset of the subject's breathing; and in responseto the sensing, delivering a stimulus to the subject's thorax or abdomenduring the subject's breathing; wherein the stimulus causes acontraction of a breathing muscle of the subject, assisting the subjectwith ventilation; and wherein at least one of the sensing and deliveringis carried out by one or more electrodes supported on a flexibleinsulating sheet, positioned within a blood vessel, and configured todeliver a stimulus.
 2. The method of claim 1, wherein sensing an onsetof the subject's breathing includes sensing an onset of an inspirationphase.
 3. The method of claim 1, wherein delivering the stimulus to thesubject's thorax or abdomen includes stimulating a diaphragm.
 4. Themethod of claim 3, wherein stimulating the diaphragm includes deliveringelectrical stimulus to the diaphragm or a nerve.
 5. The method of claim1, wherein the contraction of the breathing muscle includes acontraction of a diaphragm.
 6. The method of claim 1, wherein assistingthe subject with ventilation includes promoting regular ventilationand/or maintaining a normal ventilation drive.
 7. The method of claim 1,wherein the one or more electrodes includes an electrode pair, anddelivering the stimulus includes delivering an electrical signal via theelectrode pair.
 8. The method of claim 1, wherein sensing an onset ofthe subject's breathing includes using an accelerometer to determine amovement of the subject.
 9. An apparatus comprising: one or more sensorssuitable for detecting when a subject is breathing; a device configuredto deliver a stimulus to the subject's thorax or abdomen during at leastpart of a phase of the subject's breathing in response to a signalgenerated by the one or more sensors; and a flexible insulating sheetincluding one or more electrodes; wherein the stimulus is delivered viathe one or more electrodes positioned within a blood vessel, and iseffective to cause a contraction in a muscle of the subject.
 10. Theapparatus of claim 9, wherein the one or more sensors include anaccelerometer configured to determine a movement of the subject.
 11. Theapparatus of claim 9, wherein the one or more sensors are suitable fordetecting when a subject is inhaling or exhaling.
 12. The apparatus ofclaim 9, wherein the phase of breathing is an inspiration phase.
 13. Theapparatus of claim 9, wherein delivering stimulus to the subject'sthorax or abdomen includes delivering stimulus to a diaphragm.
 14. Theapparatus of claim 13, wherein delivering stimulus to the diaphragmincludes delivering electrical stimulus to the diaphragm or a nerve. 15.The apparatus of claim 9, wherein the contraction of the breathingmuscle includes a contraction of a diaphragm.
 16. The apparatus of claim9, wherein the device is configured to deliver stimulus during aninspiration phase of the subject's breathing.
 17. The apparatus of claim9, wherein delivering the stimulus includes delivering an electricalsignal via an electrode pair of the one or more electrodes.
 18. Theapparatus of claim 9, wherein the apparatus is at least in partimplantable in the subject's thorax or abdomen.
 19. The apparatus ofclaim 9, wherein the one or more electrodes are first electrodes, thestimulus is a first stimulus, and the apparatus further includes one ormore second electrodes; wherein the first electrodes are configured todeliver the first stimulus to a first region of the subject's thorax orabdomen; the second electrodes are configured to deliver a secondstimulus to a second region of the subject's thorax or abdomen; and thefirst stimulus causes contraction of a first portion of a respiratorymuscle, and the second stimulus causes contraction of a second portionof the respiratory muscle.
 20. The apparatus of claim 9, wherein theflexible insulating sheet includes a lead connecting the one or moreelectrodes to the device; and wherein the stimulus delivered via the oneor more electrodes includes an electrical field emitted from one surfaceof the flexible insulating sheet.
 21. The apparatus of claim 9, whereinthe flexible insulating sheet is configured to conform to a portion ofthe subject's anatomy.
 22. The method of claim 1, wherein the one ormore electrodes are components of one or more implanted sensors orimplanted devices.
 23. The method of claim 1, wherein the flexibleinsulating sheet includes a lead connecting the one or more electrodesto a stimulation source.
 24. The method of claim 1, wherein the one ormore electrodes are configured to emit an electrical field that extendsfrom only a portion of the circumference of the flexible insulatingsheet.
 25. The method of claim 1, wherein while the stimulus is beingdelivered, the one or more electrodes do not contact the breathingmuscle.
 26. The method of claim 1, wherein sensing an onset of thesubject's breathing including sensing an onset of the subject'sbreathing with one or more implanted sensors or electrodes.
 27. A methodfor treating a subject, the method comprising: sensing a subject'sbreathing; and in response to the sensing, delivering a stimulus to thesubject's thorax or abdomen during the subject's breathing, wherein: thestimulus causes a contraction of a breathing muscle of the subject,assisting the subject with ventilation; the delivering is carried out byat least one pair of electrodes supported on at least one flexibleinsulating sheet, wherein the at least one pair of electrodes ispositioned within a blood vessel and configured to emit an electricalfield that extends from only a portion of the circumference of the atleast one flexible insulating sheet; the at least one flexibleinsulating sheet includes a lead connecting the at least one pair ofelectrodes to a stimulation source; and while the stimulus is beingdelivered, the one or more electrodes do not contact the breathingmuscle.
 28. The method of claim 27, wherein the flexible insulatingsheet is configured to conform to a portion of the subject's anatomy.